This invention relates generally to the early diagnosis and treatment of cancer.
Colorectal adenocarcinoma (CRC) is one of the most common malignancies, accounting for approximately 15% of all cancer-related deaths in the US. The prevalence of CRC increases with age, the largest number of tumors occurring during the sixth decade. The expected annual incidence of this tumor has risen over the last decade and 153,760 new cases are estimated in 2007. If not diagnosed and treated early, this tumor spreads through the entire bowel wall, extends to adjacent organs and eventually metastasizes to regional lymph nodes and distant sites. The majority of deaths from CRC occur in patients with late stage tumors, which are usually incurable.
Programmed cell death (PCD) is defined as a physiological process that plays a critical role in normal development, cellular differentiation and tissue homeostasis of multicellular organisms. Dysregulation of this physiological cell death process contributes to the pathogenesis of human diseases including cancer. In addition to apoptosis (type I cell death), which has long been used as a synonym for PCD, accumulating evidence suggests that autophagy (type II cell death) also belongs to PCD. Autophagy is a highly orchestrated self-digestion process that involves multiple steps from the formation of autophagic vesicles to lysosomal degradation of the vesicles and their contents. As with apoptosis, autophagy also contributes to proper morphogenesis during development and tissue homeostasis in mature organisms.
Inhibition of apoptosis is critical to colorectal tumorigenesis. For example, overexpression of Bcl-XL in cancer may suppress the activity of the proapoptotic molecules Bax and Bak, contributing to cancer progression. It seems that, also in CRC, the dissociation of Bax and Bcl-XL promotes Bax multimerization and mitochondrial translocation, triggering apoptosis. Similarly, dysregulation of autophagy may also play a role in the pathogenesis of cancer. As an example, the autophagy activator Beclin 1 is monoallelically deleted in a high percentage of ovarian, breast, and prostate cancers. Overexpression of Beclin 1 in MCF7 cells promotes autophagy and inhibits tumor formation in nude mice. Moreover, the Beclin 1 binding protein UVRAG promotes autophagy and suppress the tumorigenesis of colon cancer cells in nude mice.
Bif-1 (Bax-Interacting Factor-1) interacts with Bax and induces its conformational change in mammalian cells during apoptosis. Knockout of Bif-1 suppresses Bax/Bak conformational change, cytochrome c release, caspase activation and cell death. The inventors have recently discovered that Bif-1 also regulates autophagy by forming a multi-protein complex with PI3KC3-Beclin1 through UVRAG and loss of Bif-1 suppresses autophagic cell death and promotes tumorigenesis (Takahashi Y, Coppola D, Matsushita N, et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 2007; 9: 1142-51 (incorporated herein by reference)). To date the expression of Bif-1 in CRC has not been reported.